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EP3344234A1 - Polymères et microsphères - Google Patents

Polymères et microsphères

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Publication number
EP3344234A1
EP3344234A1 EP16760486.7A EP16760486A EP3344234A1 EP 3344234 A1 EP3344234 A1 EP 3344234A1 EP 16760486 A EP16760486 A EP 16760486A EP 3344234 A1 EP3344234 A1 EP 3344234A1
Authority
EP
European Patent Office
Prior art keywords
polymer
microspheres
microsphere
groups
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP16760486.7A
Other languages
German (de)
English (en)
Other versions
EP3344234B1 (fr
Inventor
Clare Louise Heaysman
Andrew Lloyd
Gary Phillips
Andrew Leonard Lewis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biocompatibles UK Ltd
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Biocompatibles UK Ltd
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Publication date
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Publication of EP3344234A1 publication Critical patent/EP3344234A1/fr
Application granted granted Critical
Publication of EP3344234B1 publication Critical patent/EP3344234B1/fr
Active legal-status Critical Current
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/12—Surgical instruments, devices or methods for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels or umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
    • A61B17/12181—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices
    • A61B17/12195—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices comprising a curable material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089—Particulate, powder, adsorbate, bead, sphere
    • A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/52—Amides or imides
    • C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F220/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
    • C08F290/08—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups on to polymers modified by introduction of unsaturated side groups
    • C08F290/12—Polymers provided for in subclasses C08C or C08F
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
    • C08F290/08—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups on to polymers modified by introduction of unsaturated side groups
    • C08F290/12—Polymers provided for in subclasses C08C or C08F
    • C08F290/126—Polymers of unsaturated carboxylic acids or derivatives thereof

Definitions

  • the present invention is made in the field of embolotherapy and particularly relates to the provision of charged polymers that are suitable for use in the preparation of embolic microspheres, to the microspheres themselves and to compositions comprising these.
  • an embolic material is delivered to the blood vessels supplying a tissue, to cause an embolisation that prevents or reduces perfusion leading to local tissue necrosis.
  • This approach has gained popularity in the treatment of vascular tumours, particularly those of the liver, such as hepatocellular carcinoma (HCC).
  • the embolic material is generally delivered as a solid particle, although liquid embolics are also available.
  • Modern solid embolic materials are typically provided in the form of spherical polymeric particles, known as microspheres, which are usually provided in a range of sizes over the range 20 to 1500 microns.
  • the polymer carries a charge at physiological pH, such that drugs carrying the opposite charge can be electrostatically bound to the polymer, thereby providing improved drug loading and delivery characteristics.
  • drugs carrying the opposite charge can be electrostatically bound to the polymer, thereby providing improved drug loading and delivery characteristics.
  • Typical of this approach are the microspheres described in WO2004/071495 and in Jaiqui et al (1996) (Jiaqi, Y., et al. (1996). Nihon Igaku Hoshasen Gakkai Zasshi 56(1): 19-24.), which are anionically charged and are suited to the loading of cationic molecules.
  • Embolic microspheres of trisacryl-gelatin have also been developed (Laurent et al 1996) and are used in the clinic as so called “bland” embolic materials. These microspheres are positively charged by virtue of their gelatin content and not as a result of a charged synthetic polymer. They are not typically used for loading and delivery of drugs due to relatively poor loading and release characteristics.
  • WO06027567 addresses the problem of loading and delivery of camptothecin drugs into embolic microspheres. Although the drugs are cationically charged, the specification also mentions cationic polymers in addition to anionic ones. None of these polymers where prepared and their properties were not disclosed.
  • cationically charged microspheres have been proposed for loading and delivery of drugs, there remains a need for the provision of polymers with more suitable properties, for the preparation of cationically charged embolic compositions, such as microspheres, and for the delivery of anionically charged species, such as, La. drugs, and imaging agents.
  • the present inventors have identified a group of polymers suitable for use in embolotherapy, which are capable of loading therapeutically useful quantities of anionically charged molecules, such as drug species and imaging agents and of delivering the drugs in a useful fashion, which have properties making them appropriate for catheter delivery and can be transformed into microspheres using simple and well understood processes.
  • the present invention provides a polymer comprising a macromer, the macromer comprising 1,2 or 1,3 diol groups and pendent, cross linkable groups, the pendant cross linkable groups being cross linked by a cationically charged vinylic co- monomer of the formula I
  • X is a linear or branched Ci_6 alkylene, C 2 -6 alkenylene or C 2 _ 6 alkynylene group;
  • R 1 , IT and R J are the same or different and selected from Ci_ 4 alkyl groups; R 4 is H or Ci_ 4 alkyl.
  • the invention also provides polymeric microspheres comprising the polymer which are useful in therapy, particularly in the treatment of hypervascular tumours and in embolotherapy generally.
  • the polymer of the invention is water- swellable, but water insoluble; in the presence of aqueous liquid it will form a hydrogel.
  • Polymers of this type typically comprise between 40 and 99.9% water by weight.
  • PVA polyvinyl alcohol
  • PVA polymers having a molecular weight (weight average molecular weight) of between 1000 and 500000 Daltons may be used, although those having a molecular weight of 10,000 to 100,000 are preferred.
  • a PVA macromer comprises two or more ethylenically unsaturated, pendant cross linkable group per PVA polymer molecule.
  • the PVA macromers Preferably have about 2 to 20 such groups per molecule, for instance 5 to 10 groups.
  • These pendant groups may be vinylic or acrylic groups.
  • Pendant acrylic groups may be provided, for instance, by reacting acrylic or methacrylic acid with PVA to form ester linkages through some of the hydroxyl groups.
  • Methods for attaching vinylic groups capable of polymerisation, onto polyvinyl alcohol are described in, for instance, US4,978,713, US5,508,317 and US5,583,163.
  • the preferred macromer comprises a backbone of polyvinyl alcohol to which is linked, via a cyclic acetal linkage, an (alk)acrylaminoalkyl moiety.
  • Example 1 of this specification describes the synthesis of such a macromer.
  • Preferred macromers comprise in-chain (rather than terminal) cross linkable groups such as those of the formula II, incorporating the pendant groups.
  • Q is a linear or branched Q-Cg alkylene group
  • R 5 is H, a Ci_6 alkyl, or a C 3 _6 cycloalkyl
  • R 6 is an olefinically unsaturated electron attracting copolymerizable radical having
  • R 7 is H or a C 1-6 alkyl.
  • Q is preferably a methylene, ethylene or propylene group and most preferably a methylene group.
  • R 5 is preferably H or methyl, particularly H.
  • R 6 is preferably a group of the formula III
  • R when p is 0, then R is and when p is 1, R is a C 1-4 alkylene group.
  • the macromer preferably comprises cross-linkable groups of formula Ila
  • Q is a methylene, ethylene or propylene group and most preferably a methylene group; R 5 is H or methyl, and particularly H; and R 7 is H or methyl, and particularly H.
  • Q is a methylene group; R 5 is H and R 7 is H, as per formula lib
  • X is a linear or branched C 1-4 alkylene; preferably ethylene, propylene or buylene;
  • R 1 , 2 and R 3 J are the same or different and selected from Ci_ 4 alkyl groups; preferably methyl or ethyl
  • R 4 is H or Ci_ 4 alkyl, preferably H or methyl.
  • the cationically charged vinylic monomer is selected from (3- acrylamidobutyl)trimethyl ammonium salts, (3-acrylamidoethyl)trimethylammonium salts and, preferably (3-acrylamidopropyl)trimethylammonium salts. Salts are preferably chlorides.
  • the invention provides a polymer comprising groups of the formula Ila or lib crosslinked by a cationically charged vinylic co-monomer selected from (3-acrylamidobutyl)trimethyl ammonium salts, (3- acrylamidoethyl)trimethylammonium salts and, preferably (3- acrylamidopropyl)trimethylammonium salts.
  • a cationically charged vinylic co-monomer selected from (3-acrylamidobutyl)trimethyl ammonium salts, (3- acrylamidoethyl)trimethylammonium salts and, preferably (3- acrylamidopropyl)trimethylammonium salts.
  • Cationically charged embolic microspheres can be produced, for example, using water in oil polymerisation techniques as previously described (e.g. WO2004/071495) and as outlined below.
  • the invention therefore also provides a process for the preparation of a cationic microsphere comprising providing a macromer as described above and cross linking the macromer with a cationically charged vinylic co monomer as described above. Typically a redox catalysed process is used.
  • microspheres are produced, some of which have a core-shell type structure (see figure 1).
  • the outer shell of these microspheres can rupture, particularly in aqueous preparations, and becomes detached.
  • Such preparations are undesirable, because the small particles produced can become lodged distally from the main embolus and may lead to off target emboli and thus unpredictable embolisation.
  • microsphere compositions comprise no ruptured microspheres. The invention provides such compositions.
  • Useful polymers and particularly those of the microspheres of the present invention comprise between 5 and 75 weight% of cationic co-monomer, preferably 10 and 70, more preferably 15 to 65 and most preferably 16 to 60 weight%.
  • the weight % being expressed as the weight % of polymer, the remainder being macromer.
  • Microspheres can be separated into useful size ranges between 40 and 1500 microns, by sieving.
  • useful size ranges are 40-70, 70-150, 100-300, 300- 500, 500-700, 700-900 microns in diameter.
  • at least 70% of microspheres are within the specified range.
  • at least 80% or 90% and more preferably at least 95% This results in more predictable embolization, and ease of passage down catheters, without blockage.
  • the matrix is capable of allowing the passage of molecules of a broad range of molecular weights. Loading of the polymer with molecules such as drugs, is therefore not limited to low molecular weight species.
  • the molecular weight cut-off ranges between 40 and 250kDa. This makes the structure of the microsphere accessible to macromolecules such as peptides, proteins and nucleic acids such as DNA and RNA, as well as smaller active ingredients.
  • the molecular weight cut-off can be adjusted. Polymers having higher proportions of cationic co-monomer have a higher molecular weight cut off.
  • Preferred MW cut-offs are in the range 40-70, 70-250 and 40-250kDa. High MW cut-off matrices allow macromolecules such as DNA, RNA and proteins to be loaded into the microspheres.
  • the polymers and microspheres of the present invention can be loaded with pharmaceutically useful species, that may then be released within the body once the polymer or microsphere has been delivered, or alternatively, for example in the case of imaging agents, remain within the polymer in order to identify its position within the body.
  • the present invention therefore also provides a polymer or a microsphere as described above, comprising a pharmaceutical active or an imaging agent.
  • Polymers and microspheres provided by the present invention are capable of acting as carriers for a variety of molecules such as pharmaceutical actives.
  • These molecules may be associated with the polymer in a number of ways, for example by incorporation into the polymer matrix during the process of preparing the polymer or forming the microsphere, by absorption into the polymer after formation, by precipitation within the polymer (typically limited to molecules of very low aqueous solubility e.g. less than lOg/L) (see for example WO07090897, WO07085615) or by ionic interaction.
  • actives loaded by ionic interaction will carry an anionic charge.
  • the active preferably carries an anionic charge and is releasably bound within the polymer by ionic interactions. This allows the active to be delivered to a site within the body (for example when bound to a microsphere) and released over an extended period.
  • the loading of such compounds can be achieved quite readily by contacting the polymer or microspheres with solution of the compound in charged form.
  • the loading process proceeds most advantageously in aqueous solutions, since this approach doesn't require the later removal of solvent from the preparation.
  • the present invention particularly contemplates the loading of pharmaceutical actives that are anionically charged at physiological pH (7.4).
  • Suitable species include anionically charged (acidic) drugs, oligonucleotides, DNA, RNA, anionic polypeptides, for example.
  • Anionic imaging agents may also be loaded.
  • actives will be loaded as their charged form, such as in the form of salts (e.g. as aluminium, benzathine, calcium, ethylenediamine, lysine, meglumine, potassium, procaine, sodium, tromethamine or zinc salts).
  • salts e.g. as aluminium, benzathine, calcium, ethylenediamine, lysine, meglumine, potassium, procaine, sodium, tromethamine or zinc salts.
  • the microspheres and polymers may also be used to bind negatively charged liposomes.
  • Suitable drugs include those having one or more carboxylate groups such as indomethacin, phenylbutazone, ketoprofen, ibuprofen, diclofenac, aspirin, warfarin, furosemide as well as sulphonamides, Particularly the microspheres and polymers may be used with anticancer drugs, such as the various carboxylate containing antifolate drugs, including methotrexate, pemetrexed, ralitrexed. pralatrexed, plevitrexed and BGC- 945, which typically will be used as the salt form, e.g sodium or disodium salts.
  • carboxylate groups such as indomethacin, phenylbutazone, ketoprofen, ibuprofen, diclofenac, aspirin, warfarin, furosemide as well as sulphonamides
  • anticancer drugs such as the various carboxylate containing antifolate drugs, including methotrex
  • polymers and microspheres that are imageable within the body, typically by incorporation of one or more imaging agents into the polymer or microsphere.
  • imaging agents include one or more imaging agents into the polymer or microsphere.
  • These molecules may be associated with the microsphere in a number of ways, for example by incorporation into the polymer matrix during the process of forming it (e.g. as a microsphere), by absorption into the microsphere or polymer after formation, by precipitation within the microsphere or polymer (typically limited to molecules of low aqueous solubility e.g. less than lOg/L) or by ionic interaction.
  • Suitable imaging agents include X-ray, magnetic resonance agents, positron emission tomography (PET) agents, paramagnetic resonance agents and so on.
  • WO2015/033093 describes a particularly convenient method of rendering the polymer radiopaque, by covalently coupling a radiopaque species to a preformed microsphere.
  • the method involves coupling an aldehyde, comprising a covalently attached radiopaque species, such as a halogen (e.g. iodine or bromine), to preformed polymeric microspheres having 1,2 or 1,3 diol groups.
  • the presently described polymer may comprise PVA, to which the aldehyde may conveniently be attached as described in WO2015/033093.
  • Z is a group comprising one or more covalently bound radiopaque halogens, such as iodine.
  • Z comprises a phenyl group having 1, 2, or 3 covalently bound iodines.
  • Microspheres prepared in this manner preferably comprise at least 10% iodine by dry weight.
  • the polymer contains at least 20% iodine by dry weight and preferably greater than 30%, 40%, 50% or 60% iodine by dry weight.
  • a particularly useful radiopacity is obtained with polymers having between 30 and 50% iodine by dry weight.
  • An alternative method is to render the polymer or microsphere imageable by magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • this is achieved by incorporating into the polymer or microsphere an MRI-detectable component, such as iron for example as an iron oxide particle (e.g. as described in WO09073193), or gadolinium.
  • polymers and microspheres can be made imageable by positron emission tomography (PET).
  • PET positron emission tomography
  • PET imageable component such as F ions (provided as e.g. NaF)
  • X-ray contrast media include, La. ioxaglate, an ionic contrast agent although the microspheres can also be used with non ionic contrast agents such as iopamidol, iohexol, oxilan, iopromide and iodixanol. these compounds may be absorbed into the microspheres from aqueous solution.
  • microspheres of the present invention are typically provided sterile. Sterilisation can be achieved by methods known in the art, such as autoclaving or exposure to ionising radiation.
  • the microspheres can be provided dry (lyophilised) or as a pharmaceutical composition comprising microspheres of the invention and a pharmaceutically acceptable diluent, such as water or saline. Where they are provided dry, they are usefully provided in a sealed vial under reduced pressure (such as O.lbar or less), such that rehydration can be achieved more rapidly (as described in WO07147902).
  • Suitable pharmaceutical compositions also include compositions comprising a contrast agent, in order to assist placing of the polymer or microspheres in the body.
  • a contrast agent such as, for example iopamidol, iohexol, ioxilan, ipromide and iodixanol
  • non ionic contrast agents such as, for example iopamidol, iohexol, ioxilan, ipromide and iodixanol
  • microspheres and compositions described above may be used in a method of treatment of a patient comprising administering to the patient, cationic microspheres as described herein.
  • the patient may be in need of therapy which comprises embolization of a blood vessel.
  • the microspheres are typically introduced into a blood vessel and cause an embolus (embolotherapy).
  • the approach may use microspheres that have no added active ingredient or imaging agent or they may comprise and agent as described above.
  • the microspheres may be administered by direct injection to a site within the body of the patient, where they act as a depot of the pharmaceutical active or imaging agent, and typically do not lead to embolization.
  • the blood vessel is typically one associated with a hyper vascularised tissue, such as hepatic tumours including hepatocellular carcinoma (HCC) and hepatic metastases including metastatic colorectal carcinoma (mCRC) and neuroendocrine tumours (NETs).
  • the embolic microspheres of the invention can also be used to treat other conditions where embolisation may be effective, such as in other hypervascular conditions including uterine fibroids, prostate hyperplasia (including benign prostate hyperplasia) and for the treatment of obesity (for example by bariatric artery embolization - Weiss et al .1 Vase Interv Radiol. 2015 May; 26(51: 1 -24.
  • microspheres may also be used in procedures in which the microspheres are delivered to the site of action by direct injection.
  • One approach to this is the delivery of microspheres comprising pharmaceutical actives directly to tumours or around their periphery, by injection.
  • Figure 1 shows a microsphere prepared according to example 1 and having a disrupted outer layer.
  • Figure 2 shows optical photomicrographs of a) APTAi 6 , b) APTA 27 , c) APTA 43 and d) APTA 60 .
  • Figure 3 shows Confocal Laser Scanning Microscopy images of microspheres prepared according to Example 2 after exposure to FITC-Dextrans of a variety of molecular weights .
  • Figure 4 gives the structures of 4 sulphonic acid dyes used as model compounds in loading and elution studies (a).l-pyrenesulfonic acid sodium salt (PI): (b) 6,8-dihydroxypyrene-l,3-disulfonic acid disodium salt (P2): (c) 8-hydroxypyrene- 1,3,6-trisulfonic acid trisodium salt (P3) and (d) 1,3,6,8-pyrenetetrasulfonic acid hydrate tetrasodium salt (P4).
  • PI latihydroxypyrene-l,3-disulfonic acid disodium salt
  • P3 6-hydroxypyrene- 1,3,6-trisulfonic acid trisodium salt
  • P4 1,3,6,8-pyrenetetrasulfonic acid hydrate tetrasodium salt
  • Macromer may be prepared essentially according to Example 1 of
  • Mowiol 8-88 PVA powder (88% hydrolised, 12% acetate content, average molecular weight about 67,000D) (150g) (Clariant, Charlotte, NC USA) is added to a 2 litre glass reaction vessel. With gentle stirring, 1000ml water is added and the stirring increased to 400rpm. To ensure complete dissolution of the PVA, the temperature is raised to 99 ⁇ 9°C for 2-3 hours. On cooling to room temperature N- acryloylaminoacetaldehyde (NAAADA) (Ciba Vision, 10 Germany) (2.49g or 0.104mmol/g of PVA) is mixed in to the PVA solution followed by the addition of concentrated hydrochloric acid (100ml). The reaction proceeds at room temperature for 6-7 hours and is then stopped by neutralisation to pH 7.4 using 2.5M NaOH.
  • NAAADA N- acryloylaminoacetaldehyde
  • Diafiltration is performed using a stainless steel Pellicon 2 Mini holder stacked with 0.1m cellulose membranes having a molecular weight cut off of 3000 (Millipore Corporation, Bedford, MA USA).
  • the macromer solution is circulated over the membranes at approximately 50psi.
  • the solution has been concentrated to about 1000ml the volume is kept constant by the addition of water at the same rate that the filtrate is being collected to waste until 6000ml extra has been added. Once achieved, the solution is concentrated to 20-23% solids with a viscosity of 1700- 3400cP at 25°C.
  • Microspheres were synthesised in a redox catalysed reaction in a "water in oil” type system.
  • Organic Phase 600g n-butyl acetate and 11.5g of a 10% (w/w) cellulose acetate butyrate (CAB) in ethyl acetate were added to a glass 1L jacketed vessel connected to a heater-chiller unit and stirred at approximately 300 rpm at 25°C and purged with N 2 .
  • CAB cellulose acetate butyrate
  • Aqueous Phase A known amount of PVA macromer (21g non-volatile weight), 1.3g ammonium persulphate (APS), the appropriate amount of 3- acrylamidopropyl)trimethylammonium chloride (APTA) solution and an additional amount of purified water were mixed together and added to the reaction vessel. Water was added so that the total amount of water in the formulation was approximately 130g.
  • PVA macromer 21g non-volatile weight
  • APS ammonium persulphate
  • APTA 3- acrylamidopropyl)trimethylammonium chloride
  • TMEDA Trimethyletetramethylethlenediamine
  • APS ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylethlenediamine
  • the reaction was allowed to continue for three hours at 55°C under an inert N 2 atmosphere.
  • the microspheres were then purified by washing in ethyl acetate and acetone to remove residual CAB, before hydration and washing in water.
  • the microspheres were heat extracted by boiling in an 80 mM disodium hydrogen phosphate in 0.29 % (w/w) NaCl solution before rehydration in water, followed by equilibration in saline.
  • Microspheres were produced in a range of sizes, typically between 100 to 1200 ⁇ when hydrated in saline, and were separated into size ranges using sieves. In all formulations the total water content, weight of macromer and APS remained the same. Notation for the formulations represents the ratio of weight percentage (wt%) for APTA to macromer used in synthesis e.g. APTA 45 denotes 45 wt% APTA to 55 wt% macromer. Table 1 gives the weight percentage (wt%) of APTA versus macromer in example microsphere formulations.
  • the loading and elution properties of the microspheres of the invention were characterised using a series of commercially available pyrene sulfonic acid sodium salts as model anionic drugs.
  • the chemical structures of each dye; 1-pyrenesulfonic acid sodium salt (PI), 6,8-dihydroxypyrene-l,3-disulfonic acid disodium salt (P2), 8- hydroxypyrene-l,3,6-trisulfonic acid trisodium salt (P3) and 1,3,6,8- pyrenetetrasulfonic acid hydrate tetrasodium salt (P4) are shown in figure 4.
  • PI 1-pyrenesulfonic acid sodium salt
  • P2 6,8-dihydroxypyrene-l,3-disulfonic acid disodium salt
  • P3 8- hydroxypyrene-l,3,6-trisulfonic acid trisodium salt
  • P4 1,3,6,8- pyrenetetrasulfonic acid hydrate t
  • a measuring cylinder was used to aliquot a volume of microspheres fully hydrated in saline (e.g. 1 mL). The microspheres were then transferred to a vial and the saline solution removed. A solution of the model compound was prepared by dissolving the compound in deionised water. The solution was then added to the vial containing the slurry of microspheres. The vial was then rolled to mix at room temperature, whilst loading was monitored by removing aliquots of the loading solution.
  • the maximum binding capacity of each formulation was determined by mixing the microsphere slurry for 72 hours with excess test compound. The remaining solution was removed from the slurry and the microspheres were washed with water to remove residual unbound compound. The binding capacity was determined by complete elution in 500 mL of a saturated KCl solution in water mixed in 50:50 ratio with ethanol.
  • Microspheres of each polymer formulation were loaded with equal quantities of each dye. 1 ml samples of dye-loaded microspheres were added to 200 mL of PBS in an amber jar. The microsphere suspensions were rolled to provide continuous mixing. At each time point the eluent was sampled and assayed by UV/Vis spectrophotmetery as above. The volume of sampled eluent was replaced with fresh PBS to maintain the elution volume.
  • Figure 5 illustrates the elution profiles of each dye from APTA 43 microspheres.
  • the monovalent dye PI has the fastest rate of elution as 80% of the initial loaded amount was released within 60 minutes in comparison to 9% of the divalent dye P2 and approximately 3% of P3 and P4.
  • the elution profiles of dye PI from APTA 16 , APTA 43 and APTA 6 o are compared in figure 6.

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Abstract

L'invention concerne de nouveaux polymères cationiques qui sont appropriés pour la préparation de microsphères. Les microsphères peuvent charger et éluer des espèces anioniques telles que des médicaments et trouvent une utilisation dans i.a. l'embolothérapie.
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EP3416626A4 (fr) * 2016-02-17 2019-10-30 Biosphere Medical, Inc. Microsphères contenant des agents thérapeutiques et méthodes d'utilisation associées
WO2019035975A1 (fr) * 2017-08-16 2019-02-21 Biosphere Medical, Inc. Microsphères contenant des agents thérapeutiques et méthodes d'utilisation associées
CN109666098B (zh) * 2017-10-17 2021-03-26 中国石油化工股份有限公司 双交联网络缓膨型聚合物微球及其制备方法和应用
GB201810784D0 (en) 2018-06-29 2018-08-15 Biocompatibles Uk Ltd Radiopaque polymers
JP7391978B2 (ja) * 2019-03-22 2023-12-05 バイオコンパティブルズ ユーケー リミテッド 塞栓マイクロスフェア及び方法
US20230037198A1 (en) * 2021-07-29 2023-02-02 Varian Medical Systems, Inc. Apparatuses and methods for producing embolic particles with activated loading sites
CN114262279B (zh) * 2021-12-30 2022-12-16 上海汇禾医疗科技有限公司 一种x射线可显影分子、栓塞微球及其制备方法

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CA2996692C (fr) 2023-09-05
WO2017037276A8 (fr) 2018-03-29
KR20180050319A (ko) 2018-05-14
JP7033530B2 (ja) 2022-03-10
EP3344234B1 (fr) 2021-11-24
JP2018528305A (ja) 2018-09-27
CN107949376A (zh) 2018-04-20
WO2017037276A1 (fr) 2017-03-09
HK1254237A1 (zh) 2019-07-12
AU2016316807A1 (en) 2018-03-08
US20180250230A1 (en) 2018-09-06

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